scholarly journals Abstract PL06-03: Exploiting genome instability for new cancer therapies: PARP inhibitors and beyond

Author(s):  
Stephen P. Jackson
2021 ◽  
Vol 22 (10) ◽  
pp. 5112
Author(s):  
Lotte van Beek ◽  
Éilís McClay ◽  
Saleha Patel ◽  
Marianne Schimpl ◽  
Laura Spagnolo ◽  
...  

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.


2020 ◽  
Vol 21 (6) ◽  
pp. 755-757 ◽  
Author(s):  
Ekaterina Galkina Cleary ◽  
Fred D Ledley

Author(s):  
Alicia M. McConnell ◽  
Haley R. Noonan ◽  
Leonard I. Zon

Zebrafish are rapidly becoming a leading model organism for cancer research. The genetic pathways driving cancer are highly conserved between zebrafish and humans, and the ability to easily manipulate the zebrafish genome to rapidly generate transgenic animals makes zebrafish an excellent model organism. Transgenic zebrafish containing complex, patient-relevant genotypes have been used to model many cancer types. Here we present a comprehensive review of transgenic zebrafish cancer models as a resource to the field and highlight important areas of cancer biology that have yet to be studied in the fish. The ability to image cancer cells and niche biology in an endogenous tumor make zebrafish an indispensable model organism in which we can further understand the mechanisms that drive tumorigenesis and screen for potential new cancer therapies. Expected final online publication date for the Annual Review of Cancer Biology, Volume 5 is March 4, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.


Author(s):  
Antonella Surbone

Personalized medicine is revolutionizing cancer care and creating new expectations among oncologists and patients. At present the benefit is still marginal, however, and must be understood as incremental. In addition, cultural and resource disparities limit the sustainability of new cancer therapies on a global scale. Adequate instruments are needed to enable our exercise of sound and honest judgment in distinguishing breakthrough treatments from those that yield only marginal or doubtful improvements, and to develop strategies for formulation and correct application of balanced guidelines for sustainable cancer care. Professionalism requires that the acquisition of knowledge and skills go hand in hand with moral education in the intellectual virtues of humility, perseverance, adaptability, communicativeness, and commitment to resist self-deception or conflicts of interest. Hidden curricula undermine the moral values of medicine: these must be understood and uncovered. We should possess a special body of knowledge, skills, and values that allow us to change our practices when appropriate and to be stewards of society's limited resources through proper communication with our patients and families. In the era of personalized oncology and global issues of sustainability, professional authenticity and integrity in cancer clinical practice are key to bridging the gaps between true and false expectations of patients and the public.


2015 ◽  
Vol 113 (4) ◽  
pp. 960-965 ◽  
Author(s):  
Sarah K. C. Cheung ◽  
Po-Kai Chuang ◽  
Han-Wen Huang ◽  
Wendy W. Hwang-Verslues ◽  
Candy Hsin-Hua Cho ◽  
...  

The discovery of cancer stem cells (CSCs), which are responsible for self-renewal and tumor growth in heterogeneous cancer tissues, has stimulated interests in developing new cancer therapies and early diagnosis. However, the markers currently used for isolation of CSCs are often not selective enough to enrich CSCs for the study of this special cell population. Here we show that the breast CSCs isolated with CD44+CD24-/loSSEA-3+ or ESAhiPROCRhiSSEA-3+ markers had higher tumorigenicity than those with conventional markers in vitro and in vivo. As few as 10 cells with CD44+CD24-/loSSEA-3+ formed tumor in mice, compared with more than 100 cells with CD44+CD24-/lo. Suppression of SSEA-3 expression by knockdown of the gene encoding β-1,3-galactosyltransferase 5 (β3GalT5) in the globo-series pathway, led to apoptosis in cancer cells specifically but had no effect on normal cells. This finding is further supported by the analysis of SSEA-3 and the two related globo-series epitopes SSEA4 and globo-H in stem cells (embryonic stem cells and induced pluripotent stem cells) and various normal and cancer cells, and by the antibody approach to target the globo-series glycans and the late-stage clinical trials of a breast cancer vaccine.


2016 ◽  
Vol 27 (7) ◽  
pp. 1342-1348 ◽  
Author(s):  
M. Koehler ◽  
E.T. Donnelly ◽  
D. Kalanovic ◽  
R. Dagher ◽  
M.L. Rothenberg

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Anna Maria Mileo ◽  
Stefania Miccadei

Cancer onset and progression have been linked to oxidative stress by increasing DNA mutations or inducing DNA damage, genome instability, and cell proliferation and therefore antioxidant agents could interfere with carcinogenesis. It is well known that conventional radio-/chemotherapies influence tumour outcome through ROS modulation. Since these antitumour treatments have important side effects, the challenge is to develop new anticancer therapeutic strategies more effective and less toxic for patients. To this purpose, many natural polyphenols have emerged as very promising anticancer bioactive compounds. Beside their well-known antioxidant activities, several polyphenols target epigenetic processes involved in cancer development through the modulation of oxidative stress. An alternative strategy to the cytotoxic treatment is an approach leading to cytostasis through the induction of therapy-induced senescence. Many anticancer polyphenols cause cellular growth arrest through the induction of a ROS-dependent premature senescence and are considered promising antitumour therapeutic tools. Furthermore, one of the most innovative and interesting topics is the evaluation of efficacy of prooxidant therapies on cancer stem cells (CSCs). Several ROS inducers-polyphenols can impact CSCs metabolisms and self-renewal related pathways. Natural polyphenol roles, mainly in chemoprevention and cancer therapies, are described and discussed in the light of the current literature data.


Sign in / Sign up

Export Citation Format

Share Document